Chronic infection with hepatitis C virus (HCV) is a major cause of liver disease, but the response to antiviral therapy among African Americans is much lower than among whites. We will study how therapy affects the HCV genome and HCV RNA synthesis activity in African Americans and whites to understand this difference. Aim l: What variations are present in the complete HCV genomes of viruses infecting African Americans and whites? We hypothesize that viral variants that are less responsive to antiviral therapy are found disproportionately in African Americans. Therefore, we will sequence the entire HCV genome from 50 African Americans and 50 whites both before and after treatment. We will then align the sequences and look for differences that correlate with racial group and/or with response to antiviral therapy. Aim 2: How does the quasi-species distribution of the HCV genome vary in response to therapy? We hypothesize that therapy selects for HCV variants that are less susceptible to therapy. We will analyze quasi- species variation in 10 responders prior to therapy and in 10 non- responders both prior to and after therapy (half African Americans and half whites). Twenty isolates from each of the 5 regions that vary the most between the pre- and posttreatment samples in Aim 1 will be cloned and sequenced. We will look for common patterns of HCV genetic drift following failure of therapy and for differences in quasi- species distribution between the African Americans and whites. Aim 3: How does HCV RNA synthesis vary in response to therapy? We hypothesize that variations in the HCV RNA polymerase (RdRp) can alter RNA replication and affect response to therapy. We will assess the ability of the RdRps from each of the patients in Aim 1 before and after therapy to synthesize RNA. We will determine if RdRp activity correlates with response to therapy and how RNA synthesis changes with variation in the RdRp. These studies will provide a complete view of the HCV genome during therapy, will provide basic information about RNA replication, and will identify viral factors underlying response to therapy in African Americans and whites. This may improve treatment or guide development of new therapies for both racial groups.